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J Thorac Cardiovasc Surg 2005;130:1475-1476
© 2005 The American Association for Thoracic Surgery
Brief Communication |
a Department of Surgery, Oulu University Hospital, Clinical Research Center, University of Oulu, Oulu, Finland
c Department of Pathology, Oulu University Hospital, Clinical Research Center, University of Oulu, Oulu, Finland
d Department of Pediatrics, Oulu University Hospital, Clinical Research Center, University of Oulu, Oulu, Finland
b Department of Pathology, Kuopio University Hospital, Kuopio, Finland.
Received for publication June 13, 2005; revisions received July 7, 2005; accepted for publication July 12, 2005. * Address for reprints: Timo Kaakinen, MD, Department of Surgery, Clinical Research Center, Oulu University Hospital, PO Box 21, 90029 OYS, Finland. (Email: timo.kaakinen{at}oulu.fi).
In a previous study we have shown the neuroprotective efficacy of fructose-1,6-bisphosphate (FDP) during experimental hypothermic circulatory arrest in pigs.
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In that study tissue samples from the left parietal cerebral cortex were obtained for electron microscopy analysis and examined later. Herein, we report the findings of that analysis.
Methods
Cerebral cortex biopsy specimens of 6 animals from the FDP group and 5 animals from the control group were chosen for electron microscopy analysis. All of these animals survived 7 days after the operation and were electively killed. Details of the experiment are reported in the main article.
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The included animals in the FDP group were selected randomly. The cerebral samples (1- to 2-mm-thin sections) from the left parietal cortex were collected after the death of the animal on the 7th postoperative day. The samples were immediately fixed in a mixture of 1% glutaraldehyde and 4% formaldehyde in 0.1 mol/L phosphate buffer. The sections were further processed, examined, and photographed in a blinded fashion by a senior cell biologist (A.N.), who looked for at least 10 typical representative neurons in each tissue sample. The analysis of the photographic material was performed in a blinded fashion by a senior pathologist (H.T.) using a scoring method presented in the footnote of Table 1. Neuronal mitochondria, nuclei, cytoplasm, and endoplasmic reticulum were analyzed for ischemic injury.
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Results
The ultrastructural neuronal scores are presented in Table 1. The total neuronal damage score was lower in the FDP group (P = .002), as were the nucleus and cytoplasm scores (P = .01 and P = .011, respectively). The mitochondrion score was somewhat lower in the FDP group (P = .059). There was a significant positive correlation between the histopathologic total score of our previous study and the present electron microscopy total score (r = 0.73, P = .01).
Discussion
The key ultrastructural sign of neuronal ischemic injury is mitochondrial swelling with dilation of the intercristal spaces, eventually leading to rupture of the mitochondrial membranes. Membrane rupture releases mitochondrial Ca2+ into the cytoplasm, which, with low adenosine triphosphate concentration, is a major initiating factor of necrotic cell death. The release of mitochondrial proteins, such as cytochrome c and apoptosis-inducing factor, into the cytoplasm has been shown to induce apoptosis if adenosine triphosphate is still present in the cells in sufficient amounts. Other ultrastructural signs of neuronal injury are clumping of chromatin and nuclear rupture, along with cytoplasmic swelling. Rupture of endoplasmic reticulum and detachment of ribosomes occur after severe injury. These findings indicate loss of capability to synthesize RNA and proteins (Figure 1).
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FDP has been found to preserve and resupply cellular energy pools during ischemia-reperfusion injury.
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Intracellular increase of Ca2+ during ischemia is inhibited by FDP.
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The drug also diminishes the formation of reactive oxygen species during reperfusion.
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It seems that FDP might be able to counteract several steps in the mechanism of ischemia-reperfusion injury, a fact that makes it a promising neuroprotective agent. The present ultrastructural findings give further support to the findings of the previous studies indicating neuroprotection by FDP.
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In conclusion, the intravenous administration of two 500 mg/kg doses of FDP before and after hypothermic circulatory arrest in a surviving porcine model is associated with better ultrastructural findings in cortical neurons. These findings further suggest the neuroprotective efficacy of the drug.
Acknowledgments
We thank Dr Bruno Viglianti, Medical Assistant and Pharmacovigilance Manager, Biomedica Foscama, Ferentino, Italy, for providing us with fructose-1,6-bisphosphate (Esafosfina) and Pasi Ohtonen, MSc, for statistical assistance.
References
This article has been cited by other articles:
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  R. Pretre and M. I. Turina Deep Hypothermic Circulatory Arrest Card. Surg. Adult, January 1, 2008; 3(2008): 431 - 442. [Full Text]
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